In recent years there has been growing interest in the use of nanoparticles for drug delivery. While these nanocarriers have been shown to improve the efficacy of chemotherapy, there have been significant challenges. In cancer therapy, for example, the balance between minimizing exposure of therapeutics to healthy tissues and concurrently target a high dose of chemotherapeutics to tumors and metastases are obstacles that have been difficult to overcome. As nano-therapeutics advance to clinical trials and to commercialization, there is an urgent need to develop simple and safe approaches to image nano-carriers in vivo during the course of treatment, thereby allowing physicians and clinicians to monitor pharmacokinetics, biodistribution and efficacy of the nano-carriers in patients. Liposomes, polymers micelles, nanoparticles, and antibodies have been investigated for imaging applications with the choice of nanocarrier dependent on the drug of interest.
Diamagnetic Chemical Exchange Saturation Transfer (diaCEST) allows detection of a specific pool of exchangeable protons on a molecule. Unlike conventional paramagnetic or superparamagnetic metal-based MRI contrast agents, diaCEST contrast agents are typically small molecules or peptides that do not contain metals, and thereby are potentially less toxic and more biocompatible. Each specific pool of protons can be saturated selectively using radiofrequency pulses, and hence allow for simultaneous monitoring of multiple particle types. Particles loaded with select types of diaCEST agents could therefore be tracked at the same time in vivo.
Previously described diaCEST nanocarriers include hydrophilic diaCEST contrast agents, such as barbituric acid, encapsulated in liposomal particles. However, the use of hydrophilic agents can be problematic for formulating polymeric diaCEST particles. The interior of polymeric particles are typically composed of hydrophobic materials that are designed to encapsulate lipophilic drugs and therefore the loading efficiency of hydrophilic compounds, such as diaCEST contrast agents, can be highly restricted. In addition, the mechanism of diaCEST relies on the free exchange of protons between contrast agents and water molecules. Once the agents are loaded into polymeric particles, their access to water molecules may be severely curtailed due to the limited permeation of water into the particles, thereby diminishing the CEST contrast offered by the agents.
There is a need for nanocarriers which can efficiently incorporate diaCEST agents and allow proton exchange between the diaCEST agent and water molecules.
Therefore, it is an object of the invention to provide nano- and microcarriers which can efficiently incorporate diaCEST agents and allow proton exchange between the diaCEST agent and water molecules and methods of making and using thereof.
It is an object of the invention to provide micro- and/or nanoparticles, such as polymeric micro- and/or nanoparticles, which can efficiently incorporate diaCEST agents, particularly hydrophilic CEST agents, and allow proton exchange between the diaCEST agent and water molecules and methods of making and using thereof.
It is also an object of the invention to provide liposomes, which can efficiently incorporate diaCEST agents and allow proton exchange between the diaCEST agent and water molecules and methods of making and using thereof.